A PPAR?-humanized mouse line was generated in which the human PPAR? (hPPAR?) was expressed in the liver by placing the hPPAR? cDNA under control of the Tet-Off system of doxycyclin control and designated hPPAR?-TetOff. The hPPAR?-TetOff and wild-type mice responded to treatment with the potent PPAR? ligand Wy-14643 as revealed by the induction of genes encoding peroxisomal and mitochondrial lipid-metabolizing enzymes and lowering of serum lipids. However, only the wild-type mice and not the hPPAR?-TetOff mice exhibited hepatocellular proliferation as revealed by hepatomegally, incorporation of bromdeoxyuridine (BrdU) and induction of numerous cell cycle control genes. In addition, the hPPAR?-TetOff were resistant to Wy-14,643-induced hepatocarcinogenesis; from 20 mice, only one exhibited a carcinoma after 1 year of Wy-14,643 treatment in contrast to a 100% incidence in the wild-type mouse group. These findings suggest that the species-specific effects of fibrates are likely due to differences in the profile of genes activated by mPPAR? versus hPPAR? following fibrate treatment. This species-specific regulation of gene expression will dictate whether a fibrate drug or other PPAR? ligand exhibits carcinogenic effects on the liver. Role of PPAR? in colon carcinogenesis. There are conflicting studies showing the effects of PPAR? ligands on growth of colon tumors. To analyze the role of PPAR? in colon carcinogenesis, PPAR?-/+ and control PPAR?+/+ mice were treated with the colon-specific carcinogen azoxymethane. Azoxymethane causes an increase in ?-catenin levels and a greater incidence of colon cancer in PPAR?-/+ mice treated with azoxymethane. However, mice with preexisting damage to Apc, a regulator of ?-catenin, develop tumors in a manner insensitive to the status of PPAR?. These data show that PPAR? can suppress ?-catenin levels and colon carcinogenesis but only before damage to the APC/?-catenin pathway. These findings reveal a potentially important use for PPAR? ligands as chemopreventative agents in colon cancer.Role of PPAR? in other cancers. To determine whether PPAR? affects other types of cancers a carcinogenesis bioassay was performed using the initiator 7,12-dimethylbenz[a]anthracene (DMBA) administered by oral gavage once a week for 6 weeks and followed for a total of 25 weeks. PPAR?-/+ mice were compared with PPAR?+/+ littermate controls. PPAR?-/+ mice exhibited increased susceptibility to DMBA-induced total tumors, mammary adenocarcinomas, ovarian granulosa cell carcinomas and mouse skin papillomas. They also showed a decreased overall survival and an increase in malignant tumors and metastatic incidence. These results are the first to demonstrate an increased susceptibility in vivo of PPAR? haploinsufficiency to DMBA-mediated carcinogenesis and suggest that PPAR? may act as a tumor modifier of skin, ovarian and breast cancers. These data suggest a beneficial role for PPAR?-specific ligands in the chemoprevention of mammary, ovarian and skin carcinogenesis.